Project 3: Mechanisms of Tauopathies Project Leader: Virginia Lee Project Summary/Abstract Frontotemporal lobar degeneration (FTLD) with tau pathology (FTLD-Tau) is a group of clinically heterogeneous neurodegenerative disorders that include progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick's disease (PiD). FTLD-Tau diseases are caused by the accumulation of distinct pathological species or strains of tau (designated PSP-Tau, CBD-Tau, PiD-Tau) and mounting evidence supports a cell-to-cell spread of pathological tau as a major mechanism of disease that could explain the progression of FTLD-Tau since Alzheimer's disease (AD), another major tauopathy demonstrated stereotypical progressive spread of AD tau pathology (AD-Tau) that correlates with progressive dementia. Moreover, Projects 3 and 4 investigators and others modeled the progressive spread of pathological tau in vitro and in vivo and demonstrated that tau pathology propagates from cell-to-cell through intercellular transfer of pathological tau which acts as ?seeds? to recruit soluble tau and corrupt it into pathological tau. Thus, Project 3 proposes to test this ?transmission? hypothesis and to elucidate the mechanisms of progressive cell-to-cell spread of pathological tau in FTLD tauopathies. Since FTLD-Tau disorders are clinically diverse, we hypothesize that misfolded PSP-Tau, CBD-Tau and PiD-Tau represent different tau strains that differ in their conformations and seeding properties. To test this ?strain? hypothesis and to determine the molecular basis for FTLD-Tau strain diversity, we will purify pathological tau from well characterized CBD, PSP and PiD brains obtained from Core D that are deeply phenotypically characterized by Cores B-D and Projects 1 & 2 and use them for in vitro serial amplification experiments to characterize the biochemical and biophysical properties of tau strains. We will extend these studies to include cell biological research conducted on primary neurons from non-transgenic (Tg) and tau Tg mice to determine the molecular mechanisms of spread and toxicity. The effects of genetic factors identified in Project 2 in modifying the transmission of different tau strains will also be evaluated. Finally, Project 3 will also collaborate with Project 4 by providing well-characterized strain specific preparations for in vivo studies to test both the misfolded tau transmission and strain hypothesis.